The canonical Wnt pathway drives macropinocytosis in cancer Journal Article

Authors: Redelman-Sidi, G.; Binyamin, A.; Gaeta, I.; Palm, W.; Thompson, C. B.; Romesser, P. B.; Lowe, S. W.; Bagul, M.; Doench, J. G.; Root, D. E.; Glickman, M. S.
Article Title: The canonical Wnt pathway drives macropinocytosis in cancer
Abstract: Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the b-catenin–dependent canonical Wnt pathway, was PAK1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via APC silencing, Wnt-activated macropinocytosis stimulated uptake of luminal microbiota, a process reversed by topical pharmacologic inhibition of macropinocytosis. Our findings indicate that Wnt pathway activation drives macropinocytosis in cancer, and its inhibition could provide a therapeutic vulnerability in Wnt-driven intestinal polyposis and cancers with Wnt activation. Significance: The Wnt pathway drives macropinocytosis in cancer cells, thereby contributing to cancer growth in nutrient-deficient conditions and, in the context of colon cancer, to the early phases of oncogenesis. 2018 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 78
Issue: 16
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2018-08-15
Start Page: 4658
End Page: 4670
Language: English
DOI: 10.1158/0008-5472.can-17-3199
PROVIDER: scopus
PUBMED: 29871936
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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MSK Authors
  1. Scott W Lowe
    145 Lowe
  2. Craig Bernie Thompson
    119 Thompson
  3. Wilhelm Philipp Palm
    9 Palm